Moisture sensitive medicinal substances, which are to be administered parenterally, by infusion or injection, must be stabilized for storage. A customary stabilizing method is to dry a solution of the medicinal substance by removal of the solvent by lyophilization. For this purpose, aqueous solutions of the medicinal substances are placed in glass ampoules, glass vials, or glass bottles with puncturable caps, then frozen and freeze-dried under reduced pressure. Glass ampoules, after the drying is completed, are sealed off outside of the freeze-dryer by melting the glass shut. Vials and flasks with puncturable caps can be closed in the freeze-dryer with a freeze-dried previously mounted stopper.
Primarily important are the composition and concentration of the active substance in the solution, the type and manner of freezing, the respective temperature gradient used for the freeze-drying, as well as the final temperature, since they affect the pharmaceutical quality of the product. Furthermore, the temperature and pressure schedules, as well as the length of time used for the freeze-drying, the thickness of the solution layer to be freeze-dried, the geometry of the container with respect to the surface area in contact with the coolable and heatable container positioning plate, as well as moisture present during dealing or closure of the product, influence the pharmaceutical quality of the product.
Reliable feeding of a precise volume of solution to be dried into the container without the solution touching the ampoule neck or the vial rim, as well as the avoidance of circumstances which may lead to deposit of product residues at the neck or shoulder of the ampoules, or between the respective vial and stopper contact and sealing areas, are equally significant for maintaining a desired production output. Within the framework of being able to warrant the content of each individual vial, ampoule or bottle in a batch, and content uniformity from batch-to-batch, which contributes greatly to ensuring that the stated dosage can be withdrawn from the container, it is important to avoid risks such as which occurs when the freeze-dried solid product adheres to the vial rim and stopper sealing areas since that adversely affects product stability as a result of an inadequate seal.
The product residues at the neck of the ampoules are observable during sight inspection, which takes place when the product containers have been sealed or closed. Containers which fail the control inspection must be sorted out and removed. The lack of consistency and the shape of the product cake lead to a manufacturing loss or utilization loss where ampoules are concerned which, depending on raw material costs and manufacturing expenses, renders production variable and much more expensive. Product adherence between the sealing area of vials with their stoppers is not immediately visible during sight inspection control and is completely hidden after the protective caps are put on vials and glass bottles. This results in leakiness and permits uncontrolled passage of humid air into the vials during storage and, thus, there is a danger of hydrolytic decay of the active substances within the vials and bottles.